Parkinson's disease (PD) is a common neurologic disorder whose symptoms progress relentlessly toward severe disability and loss of quality of life. One promising potential therapy is glial cell line-derived neurotrophic factor (GDNF). GDNF is a naturally occurring growth factor that has been shown in a variety of model systems to support the survival of those dopaminergic cells that are lost in PD. Attempts to learn more about the functions of GDNF through the generation of mice lacking this factor or its receptors have been thwarted by accompanying renal and gastrointestinal abnormalities leading to early postnatal death. Through the use mice recently developed by the applicant that express Cre recombinase in dopaminergic neurons and by using powerful new chemical/genetic techniques to generate receptor inhibition, the applicant's overall goal is to generate viable mice that have cell-type specific and temporally-specific interruption of GDNF signaling. Such mice will be used as a model system to examine the role of endogenous GDNF in the postnatal development and maintenance of those cells lost in Human PD. Initial work done by the applicant in the laboratory of Dr. Ted Dawson at Johns Hopkins has generated preliminary data toward accomplishing this goal. His interest in developmental biology and neurodegenerative disease led to the formulation of this project and is derived from previous research at the NIMH, University of Maryland and Johns Hopkins University and from clinical training in neurology. The expertise in models of Parkinson's disease found in the Dawson laboratory (Sponsor) and collaborations set up with leaders in the field of growth factors (Dr. Ginty) and specific kinase inhibition (Dr. Shokat) make the potential for success in this project high. This coupled with the rich environment present in the sponsor's laboratory and in the Johns Hopkins Neurology Department in general bode well for accomplishing the applicant's ultimate goal of becoming an independent research clinician. [unreadable] [unreadable]